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Article ; Online: The Importance of Complement-Mediated Immune Signaling in Alzheimer's Disease Pathogenesis.

Batista, André F / Khan, Khyrul A / Papavergi, Maria-Tzousi / Lemere, Cynthia A

International journal of molecular sciences

2024 Volume 25, Issue 2

Abstract: As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role ...

Abstract	As an essential component of our innate immune system, the complement system is responsible for our defense against pathogens. The complement cascade has complex roles in the central nervous system (CNS), most of what we know about it stems from its role in brain development. However, in recent years, numerous reports have implicated the classical complement cascade in both brain development and decline. More specifically, complement dysfunction has been implicated in neurodegenerative disorders, such as Alzheimer's disease (AD), which is the most common form of dementia. Synapse loss is one of the main pathological hallmarks of AD and correlates with memory impairment. Throughout the course of AD progression, synapses are tagged with complement proteins and are consequently removed by microglia that express complement receptors. Notably, astrocytes are also capable of secreting signals that induce the expression of complement proteins in the CNS. Both astrocytes and microglia are implicated in neuroinflammation, another hallmark of AD pathogenesis. In this review, we provide an overview of previously known and newly established roles for the complement cascade in the CNS and we explore how complement interactions with microglia, astrocytes, and other risk factors such as TREM2 and ApoE4 modulate the processes of neurodegeneration in both amyloid and tau models of AD.
MeSH term(s)	Humans ; Alzheimer Disease/etiology ; Complement System Proteins ; Central Nervous System ; Signal Transduction ; Complement Activation
Chemical Substances	Complement System Proteins (9007-36-7)
Language	English
Publishing date	2024-01-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25020817
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Article ; Online: APOE ε4 Association With Cognition and Alzheimer Disease Biomarkers in Down Syndrome-Implications for Clinical Trials and Treatments for All.

Lemere, Cynthia A / Head, Elizabeth / Holtzman, David M

JAMA neurology

2021 Volume 78, Issue 8, Page(s) 913–915

MeSH term(s)	Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Biomarkers ; Cognition ; Down Syndrome/complications ; Down Syndrome/genetics ; Down Syndrome/therapy ; Humans
Chemical Substances	Apolipoprotein E4 ; Biomarkers
Language	English
Publishing date	2021-07-06
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2702023-X
ISSN	2168-6157 ; 2168-6149
ISSN (online)	2168-6157
ISSN	2168-6149
DOI	10.1001/jamaneurol.2021.1649
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Article ; Online: Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer's-like mouse models.

Kumar, Sathish / Lemere, Cynthia A / Walter, Jochen

Acta neuropathologica communications

2020 Volume 8, Issue 1, Page(s) 118

Abstract: The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this ... ...

Abstract	The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct age-dependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.
MeSH term(s)	Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/pathology ; Disease Models, Animal ; Down Syndrome/pathology ; Humans ; Mice ; Phosphorylation ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2020-07-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-020-00959-w
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Article ; Online: Immunotherapy for Alzheimer's disease: hoops and hurdles.

Lemere, Cynthia A

Molecular neurodegeneration

2013 Volume 8, Page(s) 36

Abstract: Alzheimer's disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-β protein ( ... ...

Abstract	Alzheimer's disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-β protein (Aβ), and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau protein, are two major pathological hallmarks of the AD brain. Aggregation, deposition, and N-terminal modification of Aβ protein and tau phosphorylation and aggregation are thought to precede the onset of cognitive decline, which is better correlated with tangle formation and neuron loss. Active and passive vaccines against various forms of Aβ have shown promise in pre-clinical animal models. However, translating these results safely and effectively into humans has been challenging. Recent clinical trials showed little or no cognitive efficacy, possibly due to the fact that the aforementioned neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy. Efforts are now underway to treat individuals at risk for AD prior to or in the earliest stages of cognitive decline with the hope of preventing or delaying the onset of the disease. In addition, efforts to immunize against tau and other AD-related targets are underway.
MeSH term(s)	Alzheimer Disease/therapy ; Alzheimer Vaccines/pharmacology ; Animals ; Humans ; Immunotherapy/methods
Chemical Substances	Alzheimer Vaccines
Language	English
Publishing date	2013-10-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/1750-1326-8-36
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Article ; Online: Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses.

Bathini, Praveen / Sun, Tao / Schenk, Mathias / Schilling, Stephan / McDannold, Nathan J / Lemere, Cynthia A

Biomolecules

2022 Volume 12, Issue 7

Abstract: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS ... ...

Abstract	Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5-6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.
MeSH term(s)	Alzheimer Disease/drug therapy ; Animals ; Blood-Brain Barrier ; Brain/physiology ; Immunity ; Immunoglobulin G/therapeutic use ; Mice ; Plaque, Amyloid
Chemical Substances	Immunoglobulin G
Language	English
Publishing date	2022-07-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12070951
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Article ; Online: Microglia Do Not Take Up Soluble Amyloid-beta Peptides, But Partially Degrade Them by Secreting Insulin-degrading Enzyme.

Fu, Hongjun / Liu, Bin / Li, Liangping / Lemere, Cynthia A

Neuroscience

2020 Volume 443, Page(s) 30–43

Abstract: Microglia play important roles in the pathogenesis of Alzheimer's disease (AD), in part, by affecting the clearance of amyloid-β (Aβ) peptides. Most studies, however, used synthetic soluble Aβ (sAβ) at higher concentrations. The exact mechanisms ... ...

Abstract	Microglia play important roles in the pathogenesis of Alzheimer's disease (AD), in part, by affecting the clearance of amyloid-β (Aβ) peptides. Most studies, however, used synthetic soluble Aβ (sAβ) at higher concentrations. The exact mechanisms underlying microglia-mediated clearance of physiological sAβ at very low concentrations remain unclear. Here we reported that there were much more Iba-1- and CD68-positive microglia and significantly less sAβ left in the brain of adult mice 5 days after the surgery of sAβ microinjection compared to 2 h after the surgery (p < 0.05). However, very few Iba-1- and CD68-positive microglia co-localized with microinjected fluorescently labeled sAβ (FLsAβ
MeSH term(s)	Alzheimer Disease ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism ; Humans ; Insulysin ; Mice ; Microglia/metabolism ; Peptide Fragments
Chemical Substances	Amyloid beta-Peptides ; Peptide Fragments ; Insulysin (EC 3.4.24.56)
Language	English
Publishing date	2020-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	196739-3
ISSN	1873-7544 ; 0306-4522
ISSN (online)	1873-7544
ISSN	0306-4522
DOI	10.1016/j.neuroscience.2020.07.020
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Article ; Online: Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer's disease.

Bairamian, Diane / Sha, Sha / Rolhion, Nathalie / Sokol, Harry / Dorothée, Guillaume / Lemere, Cynthia A / Krantic, Slavica

Molecular neurodegeneration

2022 Volume 17, Issue 1, Page(s) 19

Abstract: Background: The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at least in part by modulating ... ...

Abstract	Background: The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at least in part by modulating neuroinflammation. Given the link between neuroinflammatory changes and neuronal activity, it is plausible that gut microbiota may affect neuronal functions indirectly by impacting microglia, a key player in neuroinflammation. Indeed, increasing evidence suggests that interplay between microglia and synaptic dysfunction may involve microbiota, among other factors. In addition to these indirect microglia-dependent actions of microbiota on neuronal activity, it has been recently recognized that microbiota could also affect neuronal activity directly by stimulation of the vagus nerve. Main messages: The putative mechanisms of the indirect and direct impact of microbiota on neuronal activity are discussed by focusing on Alzheimer's disease, one of the most studied neurodegenerative disorders and the prime cause of dementia worldwide. More specifically, the mechanisms of microbiota-mediated microglial alterations are discussed in the context of the peripheral and central inflammation cross-talk. Next, we highlight the role of microbiota in the regulation of humoral mediators of peripheral immunity and their impact on vagus nerve stimulation. Finally, we address whether and how microbiota perturbations could affect synaptic neurotransmission and downstream cognitive dysfunction. Conclusions: There is strong increasing evidence supporting a role for the gut microbiome in the pathogenesis of Alzheimer's disease, including effects on synaptic dysfunction and neuroinflammation, which contribute to cognitive decline. Putative early intervention strategies based on microbiota modulation appear therapeutically promising for Alzheimer's disease but still require further investigation.
MeSH term(s)	Alzheimer Disease/pathology ; Brain/pathology ; Cognitive Dysfunction/pathology ; Gastrointestinal Microbiome/physiology ; Humans ; Microbiota ; Neuroinflammatory Diseases
Language	English
Publishing date	2022-03-05
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-022-00522-2
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Article ; Online: Developing novel immunogens for a safe and effective Alzheimer's disease vaccine.

Lemere, Cynthia A

Progress in brain research

2009 Volume 175, Page(s) 83–93

Abstract: Alzheimer's disease (AD) is the most prevalent form of neurodegeneration; however, therapies to prevent or treat AD are inadequate. Amyloid-beta (Abeta) protein accrues in cortical senile plaques, one of the key neuropathological hallmarks of AD, and is ... ...

Abstract	Alzheimer's disease (AD) is the most prevalent form of neurodegeneration; however, therapies to prevent or treat AD are inadequate. Amyloid-beta (Abeta) protein accrues in cortical senile plaques, one of the key neuropathological hallmarks of AD, and is elevated in brains of early onset AD patients in a small number of families that bear certain genetic mutations, further implicating its role in this devastating neurological disease. In addition, soluble Abeta oligomers have been shown to be detrimental to neuronal function. Therapeutic strategies aimed at lowering cerebral Abeta levels are currently under development. One strategy is to immunize AD patients with Abeta peptides so that they will generate antibodies that bind to Abeta protein and enhance its clearance. As of 1999, Abeta immunotherapy, either through active immunization with Abeta peptides or through passive transfer of Abeta-specific antibodies, has been shown to reduce cerebral Abeta levels and improve cognitive deficits in AD mouse models and lower plaque load in nonhuman primates. However, a Phase II clinical trial of active immunization using full-length human Abeta1-42 peptide and a strong Th1-biased adjuvant, QS-21, ended prematurely in 2002 because of the onset of meningoencephalitis in approximately 6% of the AD patients enrolled in the study. It is possible that T cell recognition of the human full-length Abeta peptide as a self-protein may have induced an adverse autoimmune response in these patients. Although only approximately 20% of immunized patients generated anti-Abeta titers, responders showed some general slowing of cognitive decline. Focal cortical regions devoid of Abeta plaques were observed in brain tissues of several immunized patients who have since come to autopsy. In order to avoid a deleterious immune response, passive Abeta immunotherapy is under investigation by administering monthly intravenous injections of humanized Abeta monoclonal antibodies to AD patients. However, a safe and effective active Abeta vaccine would be more cost-effective and more readily available to a larger AD population. We have developed several novel short Abeta immunogens that target the Abeta N-terminus containing a strong B cell epitope while avoiding the Abeta mid-region and C-terminus containing T cell epitopes. These immunogens include dendrimeric Abeta1-15 (16 copies of Abeta1-15 on a lysine antigen tree), 2xAbeta1-15 (a tandem repeat of two lysine-linked Abeta1-15 peptides), and 2xAbeta1-15 with the addition of a three amino acid RGD motif (R-2xAbeta1-15). Intranasal immunization with our short Abeta fragment immunogens and a mucosal adjuvant, mutant Escherichia coli heat-labile enterotoxin LT(R192G), resulted in reduced cerebral Abeta levels, plaque deposition, and gliosis, as well as increased plasma Abeta levels and improved cognition in a transgenic mouse model of AD. Preclinical trials in nonhuman primates, and human clinical trials using similar Abeta immunogens, are now underway. Abeta immunotherapy looks promising but must be made safer and more effective at generating antibody titers in the elderly. It is hoped that these novel immunogens will enhance Abeta antibody generation across a broad population and avoid the adverse events seen in the earlier clinical trial.
MeSH term(s)	Alzheimer Disease/immunology ; Alzheimer Disease/therapy ; Alzheimer Vaccines/immunology ; Amyloid beta-Peptides/immunology ; Animals ; Antigens/immunology ; Clinical Trials as Topic ; Humans ; Immunotherapy/methods
Chemical Substances	Alzheimer Vaccines ; Amyloid beta-Peptides ; Antigens
Language	English
Publishing date	2009-06-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1875-7855 ; 0079-6123
ISSN (online)	1875-7855
ISSN	0079-6123
DOI	10.1016/S0079-6123(09)17506-4
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Article ; Online: High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer's Disease Mutations.

Hinshaw, Robert G / Schroeder, Maren K / Ciola, Jason / Varma, Curran / Colletti, Brianna / Liu, Bin / Liu, Grace Geyu / Shi, Qiaoqiao / Williams, Jacqueline P / O'Banion, M Kerry / Caldarone, Barbara J / Lemere, Cynthia A

International journal of molecular sciences

2023 Volume 24, Issue 4

Abstract: Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after ... ...

Abstract	Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer's-like and wildtype littermate mice 7-8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer's model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.
MeSH term(s)	Male ; Mice ; Female ; Humans ; Animals ; Alzheimer Disease/pathology ; Protons ; Amyloid beta-Peptides/metabolism ; Dose-Response Relationship, Radiation ; Hippocampus/metabolism ; Mutation ; Mice, Transgenic
Chemical Substances	Protons ; Amyloid beta-Peptides
Language	English
Publishing date	2023-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24043615
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Article ; Online: Prescribing anti-amyloid immunotherapies to treat Alzheimer's disease: Fully informing patient decisions.

Greenberg, Barry D / Lemere, Cynthia A / Barnes, Lisa L / Hayden, Kathleen M / Kukull, Walter A / Oh, Esther S / Snyder, Peter J / Supiano, Mark / Dilworth-Anderson, Peggye

Alzheimer's & dementia (New York, N. Y.)

2023 Volume 9, Issue 4, Page(s) e12426

Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Editorial
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12426
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